Ian Flinn, MD, PhD, director, Lymphoma Research, Sarah Cannon Research Institute at Tennessee Oncology; director, Sarah Cannon Transplant and Cellular Therapy Program, TriStar Centennial, discusses the significance of the FDA approval of zanubrutinib (Brukinsa) in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

approval to zanubrutinib in patients with CLL or SLL

. The regulatory decision was based on findings from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials. SEQUOIA investigated zanubrutinib, a second-generation BTK inhibitor, vs bendamustine plus rituximab (Rituxan) in patients with previously untreated CLL or SLL. ALPINE evaluated the agent vs the BTK inhibitor ibrutinib (Imbruvica) in patients with relapsed/refractory CLL or SLL.

Dr. Flinn on the Benefits of Zanubrutinib in CLL/SLL

The FDA approval of zanubrutinib in CLL and SLL provides an additional treatment option for patients in both the frontline and relapsed settings, Flinn says. Zanubrutinib joins several treatment options that are already available for patients with CLL as another effective agent with a tolerable safety profile, Flinn explains.

Across both the ALPINE and SEQUOIA trials, adverse effects associated with zanubrutinib that occurred in at least 30% of patients were neutrophil count decrease, upper respiratory tract infection, platelet count decrease, hemorrhage, and musculoskeletal pain. Additionally, 3.7% of patients had atrial fibrillation or flutter, and 0.2% of patients had ventricular arrhythmias of grade 3 or higher.

Dr. Flinn on the Efficacy of Zanubrutinib in CLL/SLL

Although ALPINE and SEQUOIA were different studies in 2 different settings, zanubrutinib produced progression-free survival (PFS) and overall response rate (ORR) benefits in each, Flinn says. In SEQUOIA, the median PFS was not reached in patients who received zanubrutinib vs 33.7 months with chemoimmunotherapy. This PFS benefit was clinically meaningful and statistically significant, with a HR of 0.42, Flinn notes. Additionally, a separate, non-randomized cohort showed that zanubrutinib led to an ORR of 88% in patients with CLL or SLL with 17p deletion. These findings aligned with previous results of studies comparing BTK inhibitors with chemoimmunotherapy in the frontline CLL setting, Flinn explains.

More surprising results came from ALPINE, in which zanubrutinib demonstrated a median 24-month PFS rate of 78.4% and an ORR of 83.5%, vs 65.9% and 74.2%, respectively, with ibrutinib, Flinn says. In this trial, the agent also improved PFS in patients with 17p abnormalities, a historically difficult-to-treat population, Flinn concludes. 

has consulting roles with AbbVie, BeiGene, Century Therapeutics, Genentech, Genmab, Hutchison MediPharma, InnoCare Pharma, Kite Pharma, Myeloid Therapeutics, Novartis, Secura Bio, Servier Pharmaceuticals, TG Therapeutics, Vincerx Pharma, and Xencor and has received research grants from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Epizyme, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Marker Therapeutics, Merck, Millennium Pharmaceuticals, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Step Pharma, Tessa Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem, Vincerx Pharma, and 2seventy bio.

Videos

Ian Flinn, MD, PhD, discusses the significance of the FDA approval of zanubrutinib in chronic lymphocytic leukemia and small lymphocytic lymphoma.

Dr. Flinn on the FDA Approval of Zanubrutinib in CLL/SLL

 This is a perfect segue to CAR [chimeric antigen receptor] T-cell therapy. Caron, you were part of a real-world consortium data set looking at CAR T. Now, when CAR T was first studied on the ZUMA-2 clinical trial, it was for BTKi [Bruton tyrosine kinase inhibitor] intolerance or resistance. Where are we now?

 Well, I think the first place we are is that the FDA actually approved a much broader label, so it’s any relapsed or refractory mantle cell lymphoma. I think it was a very forward-thinking approval because of all of the studies that are now incorporating BTK inhibitors in the frontline setting, you don’t want patients to have to have gone through 2 lines of therapy if all of the effective therapies are being given in the front line. Thus, I think that was very forward thinking.

It is available now for patients with any relapsed/refractory mantle cell lymphoma. The vast majority of patients in the real world, as we’ve seen from 2 different series, one from Europe and one from the United States, have seen a BTKi. But what’s very interesting is there were about 18% of patients in the US series, which was about 96 patients I think in total, who had not seen a prior BTKi, and their results following brexucabtagene autoleucel were identical to patients who had seen a BTKi. I think this is the big question, is prior exposure to a BTKi important for T-cell fitness and the T-cell product, and at least from this very small cohort, it suggests that maybe it is not as important as we might have thought.

I think the data from ZUMA-2 have been replicated in these real-world series. Just like we’ve seen in large cell lymphoma, it’s very consistent. The response rates are consistent, the CR [complete response] rates of nearly 70% are consistent, and so far, what we’re seeing in terms of the 1-year progression-free and overall survival are very consistent, and the toxicities are consistent. I think 70% of patients would not have been eligible for the pivotal clinical trials. So we can now apply these therapies to a broader population of patients: patients with renal failure, heart failure, lower blood cell counts and bone marrow dysfunction, and still see the same excellent results. They continue to be really transformative, I think, for our patients.

A brief review of CAR T-cell therapy in relapsed/refractory mantle cell lymphoma as studied in the ZUMA-2 clinical trial of brexucabtagene autoleucel.

CAR T-cell Therapy in Relapsed/Refractory Mantle Cell Lymphoma 

 One of the challenges you mentioned, Michael, was that mantle cell lymphoma is still an insidious disease. It comes back.

 As we think about how our therapies shape that outcome, I wonder is there a standard of care for relapsed mantle cell lymphoma? Ian, I’ll turn to you. We can talk about frontline and what we’re doing in the frontline setting as it relates to transplant, but do we know what to do for relapsed mantle cell?

 I think the most commonly used therapies are the BTK [Bruton tyrosine kinase] inhibitors, and we now have 3 different BTK inhibitors that are approved in the second line: ibrutinib, acalabrutinib, and zanubrutinib. There are several clinical trials that show, each of these has a pivotal phase 2 trial that showed high response rates, durable remissions with a very manageable safety profile. Thus, I think that has become a very common go-to therapy for second-line therapy. There are other choices. You could use the R2 regimen as well, lenalidomide and rituximab. That also has efficacy there. But I think most people are using BTK inhibitors because it’s easier, the efficacy is very good. Finally, I shouldn’t leave out CAR [chimeric antigen receptor] T-cell therapy. Brexucabtagene has been approved for patients with 1 prior therapy, and for very high-risk patients, I think that might also be a reasonable option.

 That’s a good point. Brian, I have a quick question for you. How are we distinguishing all of these BTKs, and how will we continue to distinguish them?

 A very good question. As Dr Flinn pointed, we do have 3; ibrutinib being first to market, it’s been approved now for 7 or 8 years. And subsequently acalabrutinib and zanubrutinib as well are approved in mantle cell. I think what we’ve learned through other diseases, and there have been randomized head-to-head trials in CLL [chronic lymphocytic leukemia] and in Waldenstrom macroglobulinemia, which have demonstrated noninferiority of both acalabrutinib and zanubrutinib and improved safety profile. Although we still have patients on ibrutinib, I think we see lower atrial fibrillation rates with the newer agents, possibly lower bleeding risk, which is a known toxicity of the covalent BTK inhibitors, and in some cases different toxicities that may be unique to individual agents. But I think most of the lymphoma specialists have moved to acalabrutinib and zanubrutinib.

 Michael, there’s a new BTK on the block.

 Yes. BTK, what’s called the Bruton tyrosine kinase, was discovered in the 1950s by [Ogden] Bruton, who was an army pediatric doctor. He was a serious scholar. He found that this Bruton kinase is very important in the B-cell immune system. That protein was found and later studied by many different scholars, showing that it has a very vital link in the B-cell receptor pathway. Antigen hits the B cell, and the signals are transferred all the way to the nucleus through this B-cell receptor pathway. The BTK, Bruton tyrosine kinase, is a critical link here. If we use inhibitors to hit this link and inhibit the pathway, then growth signals are blocked and the cells will die, the lymphoma cells will die. That’s the way. This is a very interesting target.

Thus, we now have 3 BTK inhibitors. The BTK inhibitor will bind covalently with a protein BTK and will not let it go. The new kid on the block is pirtobrutinib. Instead of binding it covalently and not letting it go, this one is noncovalent binding. It binds and then lets it go, it’s like a dynamic process. This is a brand-new way to inhibit the protein, very interesting. It’s also a pill. Yesterday I presented some clinical trial data that the drug is really very good, and the response rate after many lines of therapy is over 50%. People think this is a very promising drug. I have to tell everybody, if you’re on a BTK inhibitor and you think in the future it might stop working, the next time we can use this new kid. I hope that the drug will become available to patients very soon.

 Wonderful. Brian, when you and I were talking earlier, we were talking about pirtobrutinib, and you said it’s a BTK inhibitor without BTK adverse effects.

 Tell me a little about the adverse effect profile. What are we seeing?

 What’s remarkable in all of the covalent BTK inhibitors we mentioned is that we seem to see a class effect, which is they all have some atrial fibrillation, probably ibrutinib with the most. They all have some bleeding and bruising risk. There are some other toxicities, but those sort of become accepted as hallmarks of the covalent BTK inhibitors. And what’s remarkable with the noncovalent BTK inhibitor pirtobrutinib is we don’t see these things. Thus, very low incidence, probably just background incidence of atrial fibrillation, no bleeding risk, and minor cytopenias. It seems to be remarkably well tolerated, and I think that’s really going to be important going forward because many patients do have toxicities that require them to discontinue the covalent agents.

Moving to second-line therapy for mantle cell lymphoma, experts discuss available BTK inhibitors, including the novel agent pirtobrutinib.

Second-Line Therapy for MCL: Differentiating Available BTK Inhibitors 

Ian W. Flinn, MD, PhD, director of Lymphoma Research at Sarah Cannon Research Institute, and the director for the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, discusses the utility of tafasitamab (MOR208) in patients with relapsed diffuse large B-cell lymphoma (DLBCL).

Tafasitamab would be considered for any patient with DLBCL who has relapsed and is not suitable for other therapies, says Flinn. 

CAR T-cell therapy is a very aggressive treatment option; to receive CAR T cells, patients must be almost as fit as they would need to be to undergo a stem cell transplant. The same almost holds true for patients to receive polatuzumab vedotin (Polivy), which is usually given in combination with bendamustine and rituximab (Rituxan), adds Flinn. In order to be a candidate to receive that combination, patients must have a good hematologic function.

For some patients,that is not a realistic scenario. For example, they could have cytopenias or have previously received multiple chemotherapies, and giving more chemotherapy is not an appropriate approach for them, says Flinn.

As such, tafasitamab, in combination with lenalidomide (Revlimid), is a very appropriate treatment option for that group of patients, concludes Flinn.

Ian W. Flinn, MD, PhD, discusses the utility of tafasitamab (MOR208) in patients with relapsed diffuse large B-cell lymphoma (DLBCL).

Dr. Flinn on the Utility of Tafasitamab in Relapsed/Refractory DLBCL

Ian Flinn, MD, PhD, director of the Blood Cancer Research Program, Sarah Cannon Research Institute, discusses the iNNOVATE trial in Waldenstrom macroglobulinemia.

There have been many updates in hematology in the past year, one of which came from the results of the iNNOVATE trial in Waldenstrom macroglobulinemia. In the trial, patients either received rituximab (Rituxan) or rituximab and ibrutinib (Imbruvica). Patients enrolled in the trial were very heterogenous, explains Flinn. Previously untreated patients, as well as those who received prior therapy, were eligible for the trial.

There was a substantial improvement in both the depth of response and overall response in patients who received the combination compared with single-agent rituximab, says Flinn. In addition to the response rate, there was a substantial difference in progression-free survival between the 2 arms.

Surprisingly, the incidence of atrial fibrillation was 12% in the ibrutinib arm compared to 1% with single-agent rituximab. Though ibrutinib is associated with atrial fibrillation, physicians have never seen it manifest on such a large scale. This may be attributed to a foundational difference in the disease, explains Flinn.

Dr. Flinn on the iNNOVATE Trial in Waldenstrom Macroglobulinemia

Ian Flinn, MD, PhD, director of the Blood Cancer Research Program, Sarah Cannon Research Institute, discusses the RELEVANCE trial in follicular lymphoma.

One of the key updates in follicular lymphoma, says Flinn, were the findings from the RELEVANCE trial. The phase III trial compared rituximab (Rituxan) and chemotherapy with rituximab and lenalidomide (Revlimid). The trial was based on phase II data that suggested that rituximab plus lenalidomide (R

) had very high complete remission (CR) rates and a tolerable safety profile.

 regimen showed a CR or unconfirmed CR rate of 48% compared with 53% for rituximab/chemotherapy (

 = .13). The objective response rate was 84% and 89% for the R

 regimen and rituximab/chemotherapy combination, respectively. The 3-year duration of response was 77% with R

 compared with 74% for rituximab/chemotherapy.

Although the trial failed to meet its primary endpoint of R

 superiority, response rates between the 2 arms were nearly identical, says Flinn. It also offers a non-chemotherapy approach for the frontline treatment of follicular lymphoma. This may be a valuable approach for patients who are looking to avoid the toxicities that are associated with rituximab/chemotherapy. Flinn notes that the toxicities were different between the 2 arms; there was a little bit more febrile neutropenia on the rituximab/chemotherapy arm and more rashes on the R

Ian Flinn, MD, PhD

Articles

Dr. Flinn on the FDA Approval of Zanubrutinib in CLL/SLL

CAR T-cell Therapy in Relapsed/Refractory Mantle Cell Lymphoma

Second-Line Therapy for MCL: Differentiating Available BTK Inhibitors

Dr. Flinn on the Utility of Tafasitamab in Relapsed/Refractory DLBCL

Dr. Flinn on the iNNOVATE Trial in Waldenstrom Macroglobulinemia

Dr. Flinn on the RELEVANCE Trial in Follicular Lymphoma